During normal pregnancy, a semiallogeneic fetus is not rejected by the maternal immune system. The unique pattern of class I major histocompatibility complex (MHC) antigen expression seen at the human maternal/fetal interface is thought to be vital for proper fetal immune status. The lack of polymorphic class I and II MHC antigens on trophoblasts the only fetal tissue in direct contact with the mother, is likely to be at least a part of the explanation of fetal evasion of allograft rejection. The observation that the HLA-G-encoded class I MHC molecule is present on certain subpopulations of cytotrophoblasts suggests this nonpolymorphic molecule may have a role in the maternal/fetal immune response and, possibly, have a role in maintaining the immunoprivileged status of the fetus. In this request for continued support, we propose to examine the regulation and immunological role of class I MHC gene expression at the maternal/fetal interface using transgenic mice. Transgenic mice carrying a genomic fragment from the HLA-G locus express the HLA-G gene in their extraembryonic tissue in a pattern similar to the extraembryonic expression of HLA-G during human gestation. This transgenic model system will be used to delineate the cis-acting DNA elements required for proper spatial and temporal (developmental) expression of HLA-G in extraembryonic tissue. In addition, transgenic mice will be used to assess the recognition of HLA-G by T cells and whether HLA-G transgenic mice are tolerant to HLA-G. If tolerance to HLA-G is demonstrated, we will determine the role of the thymus in the induction of this tolerance. We also propose to examine the effect of extraembryonic expression of HLA-G on the maternal decidual T cell population. Finally, the role of HLA-G expressed at the maternal/fetal interface in presenting foreign antigen to the maternal immune system will be assessed.